Hippocampal and cortical activities reflect early hyperexcitability in an Alzheimer's mouse model

Early stages of Alzheimer's disease are marked by brain hyperexcitability, evidenced by subclinical epileptiform features suggesting an excitation-inhibition imbalance. Clinically translatable biomarkers for early detection of excitation-inhibition changes at the network level, however, are lacking. We investigated the functional excitation-inhibition ratio, theta-gamma phase-amplitude coupling and epileptiform features in hippocampal and cortical local field potentials recorded weekly in freely behaving male APPswe/PS1dE9 (APP/PS1) mice (n = 10) and wild-type controls (n = 10) between 3 and up to and including 11 months of age. APP/PS1 mice exhibited a shift towards increased excitation, reflected in the elevated functional excitation-inhibition ratio emerging most prominently in the hippocampus at 6 months. Additionally, elevated population spiking activity and age-related impairments in theta-gamma phase-amplitude coupling were observed in the local field potentials of APP/PS1 mice in both the hippocampus and the cortex. Importantly, the functional excitation-inhibition ratio correlated positively with elevated population spiking activity in both brain regions in APP/PS1 mice. Our findings highlight the functional excitation-inhibition ratio as a promising biomarker of hippocampal and cortical network disinhibition and hyperexcitability in APP/PS1 mice, with potential value as an early disease marker in Alzheimer's disease.